Effects of TX-001HR on Uterine Bleeding Rates in Menopausal Women with Vasomotor Symptoms

Transcription

1 Effects of TX-001HR on Uterine Bleeding Rates in Menopausal Women with Vasomotor Symptoms Photo (compulsory) Steven R Goldstein, MD 1 ; Ginger D Constantine, MD 2 ; David F Archer, MD 3 ; James H Pickar, MD 4 ; Shelli Graham, PhD 5 ; Brian Bernick, MD 5 ; Sebastian Mirkin, MD 5 1 New York University School of Medicine, New York, NY; 2 EndoRheum Consultants, LLC, Malvern, Pal 3 Eastern Virginia Medical School, Norfolk, VA; 4 Columbia University Medical Center, New York, NY; 5 TherapeuticsMD, Boca Raton, FL

2 Disclosures Advisory board: Abbvie, Allergan, IBSA, Pfizer, and TherapeuticsMD Consultant: Cook ObGyn and Cooper Surgical

3 Uterine Bleeding with VMS Treatments Use of compounded bioidentical HT (CBHT) has become highly prevalent in the US since the 2002 WHI report 1 An estimated 1 to 2.5 million US women use unapproved compounded products, 1 representing up to 21 to 39 million prescriptions annually, 1,2 becoming a leading therapy in the US Reports 3-6 and a NAMS survey (n=1064) 7 suggest an increase in uterine bleeding and endometrial hyperplasia/cancer with CBHT Vaginal or uterine bleeding regardless of therapy employed may be a sign of abnormal pathology and will lead to additional evaluation Compared with progestins, progesterone may have less impact on the angiogenic/antiangiogenic balance in the endometrium 8 No HT product combining 17β-estradiol and progesterone has been approved HT: hormone therapy; NAMS: North American Menopause Society; VMS: vasomotor symptoms 1. Pinkerton J and Santoro N. Menopause 2015;22: Pinkerton J and Constantine G. Menopause 2016;23: Eden JA et al. Med J Aust 2007;187: Davis R et al. J Womens Health (Larchmt) 2014;23: Dezman VL et al. Int J Gynecol Cancer 2015;25 Suppl 1: Gersak K et al. Climacteric 2014;17(Suppl 1): Gass M et al. Menopause 2015:22; Archer DF. Menopause 2011;18:

4 REPLENISH Trial Safety endpoints: To evaluate endometrial safety (primary) and uterine bleeding (secondary) of four daily TX-001HR (E2/P4) doses versus placebo given in the REPLENISH trial to treat moderate-to-severe vasomotor symptoms TX-001HR (TherapeuticsMD, Boca Raton, FL) is an investigational combination of 17β-estradiol and progesterone (sometimes referred to as bioidentical hormones) in a single, oral, softgel capsule Design: Randomized, double-blind, placebo-controlled, multicenter, phase 3 trial of TX-001HR in menopausal women with an intact uterus (NCT ) 1-year endometrial safety study 12-week efficacy substudy for the treatment of vasomotor symptoms Lobo RA et al. Obstet Gynecol 2018, In press.

5 Study Design: Randomization VMS substudy (12 wks) 7/day or 50/week moderate-to-severe hot flushes Randomized 1:1:1:1:1 Treatment Groups 1 mg E2/100 mg P4 0.5 mg E2/100 mg P4 0.5 mg E2/50 mg P mg E2/50 mg P4 Placebo General study (12 mos) Did not qualify for VMS substudy Randomized 1:1:1:1 Both populations were assessed for general and endometrial safety Endometrial bleeding profiles, including cumulative amenorrhea (no bleeding or spotting) were assessed over thirteen 28-day cycles between treatment groups All women completed diaries of daily bleeding (requiring sanitary protection) and spotting (not requiring sanitary protection) up to month 12 Lobo RA et al. Obstet Gynecol 2018, In press.

6 Disposition and Demographics 69% of women completed at 52 weeks Mean age: 55 years (40 66) Mean BMI: 27 kg/m 2 65% were white and 32% black Subjects screened for eligibility n=5020 Randomized to treatment n=1845 Screen failures n=3175 Did not take 1 capsule n=10 Population, n (%) Safety Completed at 52 weeks Discontinued Adverse event Lost to follow-up Subject withdrawal Other* 1 mg E2/ 100 mg P (68.4) 131 (31.6) 46 (11.1) 27 (6.5) 36 (8.7) 22 (5.3) 0.5 mg E2/ 100 mg P (71.9) 119 (28.1) 33 (7.8) 30 (7.1) 42 (9.9) 14 (3.3) 0.5 mg E2/ 50 mg P (74.1) 109 (25.9) 34 (8.1) 26 (6.2) 29 (6.9) 20 (4.8) 0.25 mg E2/ 50 mg P (66.3) 143 (33.7) 41 (9.7) 38 (9.0) 31 (7.3) 33 (7.8) Placebo (61.6) 58 (38.4) 10 (6.6) 17 (11.3) 13 (8.6) 18 (11.9) Endometrial Safety *Other included investigator decision, lack of efficacy, protocol deviation and other. Lobo RA et al. Obstet Gynecol 2018, In press.

7 Percent Cumulative Amenorrhea Cumulative amenorrhea from cycle 1 to 13 was high with TX-001HR (56 73%), but lower than with placebo (81%), and increased over time >90% had amenorrhea during cycle *P<0.05; P<0.01; P<0.001 vs placebo. Cycles are 28 days in length Lobo RA et al. Obstet Gynecol 2018, In press. * * * * * * * Cycle * 1 mg E2/100 mg P4 0.5 mg E2/100 mg P4 0.5 mg E2/50 mg P mg E2/50 mg P4 Placebo *

8 Percent Cumulative No Bleeding Women with no bleeding was high (74 90%) with TX-001HR * * * * * * Cycle * 1 mg E2/100 mg P4 0.5 mg E2/100 mg P4 0.5 mg E2/50 mg P mg E2/50 mg P4 Placebo *P<0.05; P 0.01; P<0.001 vs placebo. Cycles are 28 days in length

9 Percent Amenorrhea per Quarter Percentages of women with amenorrhea 70 80% with TX-001HR vs 89% with placebo during quarter 1 Increased to 83 93% with TX-001HR vs 95% with placebo during quarter * * * Amenorrhea * 1 mg E2/100 mg P4 0.5 mg E2/100 mg P4 0.5 mg E2/50 mg P mg E2/50 mg P4 Placebo Quarter *P<0.05; P<0.01; P<0.001 vs placebo.

10 Endometrial Safety Endometrial hyperplasia incidence was 0% No endometrial malignancies detected with any TX-001HR dose or placebo Treatment, n (%) Estradiol/Progesterone 1 mg/100 mg 0.5 mg/100 mg 0.5 mg/50 mg 0.25 mg/50 mg Placebo n Hyperplasia at 12 months Incidence rate 1-sided upper 95% CI 1.06% 0.98% 0.97% 1.09% 3.20% Proliferative endometrium* Screening Month 12 Endometrial polyps Screening Month 12 2 (0.7) 8 (2.9) 5 (1.8) 4 (1.4) 5 (1.7) 5 (1.7) 7 (2.3) 6 (2.0) *Includes proliferative endometrium and disordered proliferative endometrium. 2 (0.7) 1 (0.3) 5 (1.6) 10 (3.3) 1 (0.4) 3 (1.1) 5 (1.8) 7 (2.6) Lobo RA et al. Obstet Gynecol 2018, In press.

11 Adverse Events Related to Bleeding Few bleeding adverse events were reported* TX-001HR: % Placebo: 0.7% Discontinuation due to bleeding was low TX-001HR: % Placebo: 0% *Including postmenopausal hemorrhage, uterine hemorrhage, or vaginal hemorrhage.

12 Cumulative Amenorrhea Rates with HT Based upon prescribing information or clinical data; not head-to-head comparison Products Doses Cumulative Amenorrhea (%) Prempro (CEE/MPA) mg / 5 mg mg / 2.5 mg 0.45 mg / 1.5 mg 0.3 mg / 1.5 mg Cycle 1 to Cycle 13 Activella (E2/NETA) 2 1 mg / 0.5 mg 49 Angeliq (E2/DRSP) 3 1 mg / 0.5 mg 45 TX-001HR (E2/P4) 4 1 mg / 100 mg 0.5 mg / 100 mg 0.5 mg / 50 mg 0.25 mg / 50 mg Placebo CEE: conjugated equine estrogens; DRSP: drospirenone; MPA: medroxyprogesterone acetate; NETA: norethisterone acetate. 1. Prempro tablets prescribing information. Wyeth Pharmaceuticals. 2. Activella tablets prescribing information. Novo Nordisk FemCare AG. 3. Angeliq Tablets prescribing information. Berlex. 4. Lobo RA et al. Obstet Gynecol 2018, In press.

13 Conclusions Amenorrhea rates were high in users of TX-001HR Higher rates with TX-001HR doses than other approved hormone therapy products* This clinical trial provided evidence of endometrial safety with TX-001HR at 12 months Absence of endometrial hyperplasia and cancer here should be considered in light of case reports of endometrial hyperplasia and cancer observed with compounded bioidentical HT use 1-4 Endometrial safety observed with TX-001HR highlights the need for compounded bioidentical HT safety studies given their potential risks If approved, TX-001HR may be an appropriate alternative combination HT with E2/P4 for treating moderate-to-severe VMS Especially in the estimated millions of menopausal women currently using less regulated and unapproved compounded bioidentical HT *Not evaluated in head-to-head comparison studies. Compounded bioidentical HT use ranged from unknown to several years; most were ~2 years. 1. Eden JA, et al. Med J Aust 2007;187: Davis R, et al. J Womens Health (Larchmt) 2014;23: Dezman VL, et al. Int J Gynecol Cancer 2015;25 Suppl 1: Gersak K et al. Climacteric 2014;17(Suppl 1):58-59.